Lung cancer is one of the most common malignancies in HIV-infected patients. Prevalence and mortality outcomes are higher in HIV-infected populations than in noninfected patients. There are several oral agents available for patients who harbor specific mutations, but little is known about mutations and affected pathways in HIV-infected patients with lung cancer. Recent trials have facilitated the inclusion of HIV-infected patients in clinical trials, but the population is remains underrepresented in oncology trials. Here, we review the literature on lung cancer in HIV-infected patients, and discuss common mutations in lung cancer and HIV-infected patients, the role of mutational analysis, and the potential role of targeted therapy in the treatment of lung cancer in HIV-infected populations.

Click on the PDF icon at the top of this introduction to read the full article.

Lung cancer is one of the most common malignancies in HIV-infected patients. Prevalence and mortality outcomes are higher in HIV-infected populations than in noninfected patients. There are several oral agents available for patients who harbor specific mutations, but little is known about mutations and affected pathways in HIV-infected patients with lung cancer. Recent trials have facilitated the inclusion of HIV-infected patients in clinical trials, but the population is remains underrepresented in oncology trials. Here, we review the literature on lung cancer in HIV-infected patients, and discuss common mutations in lung cancer and HIV-infected patients, the role of mutational analysis, and the potential role of targeted therapy in the treatment of lung cancer in HIV-infected populations.

Click on the PDF icon at the top of this introduction to read the full article.

Lung cancer is one of the most common malignancies in HIV-infected patients. Prevalence and mortality outcomes are higher in HIV-infected populations than in noninfected patients. There are several oral agents available for patients who harbor specific mutations, but little is known about mutations and affected pathways in HIV-infected patients with lung cancer. Recent trials have facilitated the inclusion of HIV-infected patients in clinical trials, but the population is remains underrepresented in oncology trials. Here, we review the literature on lung cancer in HIV-infected patients, and discuss common mutations in lung cancer and HIV-infected patients, the role of mutational analysis, and the potential role of targeted therapy in the treatment of lung cancer in HIV-infected populations.

Click on the PDF icon at the top of this introduction to read the full article.

Eltrombopag tablets

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved an expanded use for eltrombopag (Promacta) to include children 1 year of age and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The updated label also includes a new oral suspension formulation of eltrombopag designed for younger children who may not be able to swallow tablets.

Eltrombopag was previously approved by the FDA in a tablet formulation in June 2015 for ITP patients ages 6 and older and in 2008 for use in adults with ITP.

The label expansion of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT or AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient (1%).

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Prescribing information

The recommended dose and schedule of eltrombopag for pediatric patients age 6 and older is 50 mg daily or 25 mg daily of the tablet formulation for patients with East Asian ancestry. The recommended dose for all patients age 1 to 5 years is 25 mg daily of the powder for oral suspension formulation.

Eltrombopag is marketed as Promacta in the US and Revolade in most other countries. For more information on the drug, see the full prescribing information.

Eltrombopag tablets

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved an expanded use for eltrombopag (Promacta) to include children 1 year of age and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The updated label also includes a new oral suspension formulation of eltrombopag designed for younger children who may not be able to swallow tablets.

Eltrombopag was previously approved by the FDA in a tablet formulation in June 2015 for ITP patients ages 6 and older and in 2008 for use in adults with ITP.

The label expansion of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT or AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient (1%).

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Prescribing information

The recommended dose and schedule of eltrombopag for pediatric patients age 6 and older is 50 mg daily or 25 mg daily of the tablet formulation for patients with East Asian ancestry. The recommended dose for all patients age 1 to 5 years is 25 mg daily of the powder for oral suspension formulation.

Eltrombopag is marketed as Promacta in the US and Revolade in most other countries. For more information on the drug, see the full prescribing information.

Eltrombopag tablets

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved an expanded use for eltrombopag (Promacta) to include children 1 year of age and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The updated label also includes a new oral suspension formulation of eltrombopag designed for younger children who may not be able to swallow tablets.

Eltrombopag was previously approved by the FDA in a tablet formulation in June 2015 for ITP patients ages 6 and older and in 2008 for use in adults with ITP.

The label expansion of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT or AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient (1%).

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Prescribing information

The recommended dose and schedule of eltrombopag for pediatric patients age 6 and older is 50 mg daily or 25 mg daily of the tablet formulation for patients with East Asian ancestry. The recommended dose for all patients age 1 to 5 years is 25 mg daily of the powder for oral suspension formulation.

Eltrombopag is marketed as Promacta in the US and Revolade in most other countries. For more information on the drug, see the full prescribing information.

Toxoplasma gondii

Image by Ke Hu & John Murray

Researchers say they have determined the structure of an enzyme that is vital to the infectious behavior of the parasites that cause toxoplasmosis and malaria.

And this has revealed a potentially druggable target that could prevent the parasites from entering and exiting host cells.

Sebastian Lourido, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described this work in PNAS.

The researchers noted that the toxoplasmosis-causing parasite Toxoplasma gondii is closely related to the malaria-causing Plasmodium parasites. So research on T gondii can provide insights into Plasmodium’s inner workings.

For this study, Dr Lourido and his colleagues wanted to learn more about calcium-dependent protein kinases (CDPKs), enzymes that are needed for T gondii and related parasites to invade and exit host cells, move, and reproduce.

To investigate CDPKs, the team used single-domain antibody fragments derived from alpacas. Unlike humans, whose antibodies have a heavy chain and a light chain, alpacas create heavy-chain-only antibodies, which can be engineered into even smaller antibody fragments known as nanobodies.

Alpaca nanobodies have a unique shape that allows them to reach into a protein’s nooks and crannies, which are inaccessible to conventional antibodies.

The researchers identified a nanobody against the T gondii enzyme CDPK1 that binds the kinase’s regulatory domain and revealed a previously unappreciated feature of its activation.

The nanobody, called 1B7, stabilizes CDPK1 in a conformation that allowed the researchers to determine the kinase’s structure and describe the nanobody’s interaction with the molecule.

With the structure in hand, the team created long-timescale molecular dynamics simulations of the enzyme, to model the events leading to kinase inactivation.

Structural homology between CDPKs and the calmodulin-dependent kinases (CaMKs) found in humans led to earlier assumptions that both types of enzymes are activated in a similar fashion. But this new work shows otherwise.

A CaMK is activated when a wedge holding it in an inactive state is knocked away. In contrast, Dr Lourido likened a CDPK’s active conformation to a broken arm that must be splinted in two places to maintain its integrity.

When the rigid splint is removed, the kinase loses its structural ability to function. By blocking CDPK1’s regulatory domain, the 1B7 nanobody inhibits the kinase by preventing the enzyme’s “splint” from attaching.

“This work reveals something interesting about this class of enzymes,” Dr Lourido said. “It’s the first time a calcium-regulated kinase has been shown to be activated in this manner. The principle that we identify is really important. We’ve found a new vulnerability within an enzyme that we know is extremely important to this class of parasites, including Plasmodium . . . , and is absent from humans.”

Because humans lack similar kinases, drugs that target CDPKs would not affect host cells.

“The location where 1B7 binds to CDPK1 is a new drug target that people had not considered before,” said study author Jessica Ingram, PhD, also of the Whitehead Institute for Biomedical Research.

“We’d like to do some drug screens in the presence of the nanobody to see if we can find small molecules that bind in the same way. We could also look at other nanobodies against other kinases to see if this is applicable to other parasites and systems.”

Toxoplasma gondii

Image by Ke Hu & John Murray

Researchers say they have determined the structure of an enzyme that is vital to the infectious behavior of the parasites that cause toxoplasmosis and malaria.

And this has revealed a potentially druggable target that could prevent the parasites from entering and exiting host cells.

Sebastian Lourido, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described this work in PNAS.

The researchers noted that the toxoplasmosis-causing parasite Toxoplasma gondii is closely related to the malaria-causing Plasmodium parasites. So research on T gondii can provide insights into Plasmodium’s inner workings.

For this study, Dr Lourido and his colleagues wanted to learn more about calcium-dependent protein kinases (CDPKs), enzymes that are needed for T gondii and related parasites to invade and exit host cells, move, and reproduce.

To investigate CDPKs, the team used single-domain antibody fragments derived from alpacas. Unlike humans, whose antibodies have a heavy chain and a light chain, alpacas create heavy-chain-only antibodies, which can be engineered into even smaller antibody fragments known as nanobodies.

Alpaca nanobodies have a unique shape that allows them to reach into a protein’s nooks and crannies, which are inaccessible to conventional antibodies.

The researchers identified a nanobody against the T gondii enzyme CDPK1 that binds the kinase’s regulatory domain and revealed a previously unappreciated feature of its activation.

The nanobody, called 1B7, stabilizes CDPK1 in a conformation that allowed the researchers to determine the kinase’s structure and describe the nanobody’s interaction with the molecule.

With the structure in hand, the team created long-timescale molecular dynamics simulations of the enzyme, to model the events leading to kinase inactivation.

Structural homology between CDPKs and the calmodulin-dependent kinases (CaMKs) found in humans led to earlier assumptions that both types of enzymes are activated in a similar fashion. But this new work shows otherwise.

A CaMK is activated when a wedge holding it in an inactive state is knocked away. In contrast, Dr Lourido likened a CDPK’s active conformation to a broken arm that must be splinted in two places to maintain its integrity.

When the rigid splint is removed, the kinase loses its structural ability to function. By blocking CDPK1’s regulatory domain, the 1B7 nanobody inhibits the kinase by preventing the enzyme’s “splint” from attaching.

“This work reveals something interesting about this class of enzymes,” Dr Lourido said. “It’s the first time a calcium-regulated kinase has been shown to be activated in this manner. The principle that we identify is really important. We’ve found a new vulnerability within an enzyme that we know is extremely important to this class of parasites, including Plasmodium . . . , and is absent from humans.”

Because humans lack similar kinases, drugs that target CDPKs would not affect host cells.

“The location where 1B7 binds to CDPK1 is a new drug target that people had not considered before,” said study author Jessica Ingram, PhD, also of the Whitehead Institute for Biomedical Research.

“We’d like to do some drug screens in the presence of the nanobody to see if we can find small molecules that bind in the same way. We could also look at other nanobodies against other kinases to see if this is applicable to other parasites and systems.”

Toxoplasma gondii

Image by Ke Hu & John Murray

Researchers say they have determined the structure of an enzyme that is vital to the infectious behavior of the parasites that cause toxoplasmosis and malaria.

And this has revealed a potentially druggable target that could prevent the parasites from entering and exiting host cells.

Sebastian Lourido, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described this work in PNAS.

The researchers noted that the toxoplasmosis-causing parasite Toxoplasma gondii is closely related to the malaria-causing Plasmodium parasites. So research on T gondii can provide insights into Plasmodium’s inner workings.

For this study, Dr Lourido and his colleagues wanted to learn more about calcium-dependent protein kinases (CDPKs), enzymes that are needed for T gondii and related parasites to invade and exit host cells, move, and reproduce.

To investigate CDPKs, the team used single-domain antibody fragments derived from alpacas. Unlike humans, whose antibodies have a heavy chain and a light chain, alpacas create heavy-chain-only antibodies, which can be engineered into even smaller antibody fragments known as nanobodies.

Alpaca nanobodies have a unique shape that allows them to reach into a protein’s nooks and crannies, which are inaccessible to conventional antibodies.

The researchers identified a nanobody against the T gondii enzyme CDPK1 that binds the kinase’s regulatory domain and revealed a previously unappreciated feature of its activation.

The nanobody, called 1B7, stabilizes CDPK1 in a conformation that allowed the researchers to determine the kinase’s structure and describe the nanobody’s interaction with the molecule.

With the structure in hand, the team created long-timescale molecular dynamics simulations of the enzyme, to model the events leading to kinase inactivation.

Structural homology between CDPKs and the calmodulin-dependent kinases (CaMKs) found in humans led to earlier assumptions that both types of enzymes are activated in a similar fashion. But this new work shows otherwise.

A CaMK is activated when a wedge holding it in an inactive state is knocked away. In contrast, Dr Lourido likened a CDPK’s active conformation to a broken arm that must be splinted in two places to maintain its integrity.

When the rigid splint is removed, the kinase loses its structural ability to function. By blocking CDPK1’s regulatory domain, the 1B7 nanobody inhibits the kinase by preventing the enzyme’s “splint” from attaching.

“This work reveals something interesting about this class of enzymes,” Dr Lourido said. “It’s the first time a calcium-regulated kinase has been shown to be activated in this manner. The principle that we identify is really important. We’ve found a new vulnerability within an enzyme that we know is extremely important to this class of parasites, including Plasmodium . . . , and is absent from humans.”

Because humans lack similar kinases, drugs that target CDPKs would not affect host cells.

“The location where 1B7 binds to CDPK1 is a new drug target that people had not considered before,” said study author Jessica Ingram, PhD, also of the Whitehead Institute for Biomedical Research.

“We’d like to do some drug screens in the presence of the nanobody to see if we can find small molecules that bind in the same way. We could also look at other nanobodies against other kinases to see if this is applicable to other parasites and systems.”

Clostridium difficile spores

The US Food and Drug Administration (FDA) has granted orphan designation to SER-109 for the prevention of recurrent Clostridium difficile infection (CDI) in adults.

SER-109 is a microbiome therapeutic designed to treat recurrent CDI by correcting dysbiosis of the human microbiome.

In a single dose of 4 capsules, SER-109 re-introduces an ecology of purified bacterial spores that should restore the microbiome to a healthy state, allowing it to carry out key biological functions, including resisting Clostridium difficile.

“SER-109 is intended to re-introduce essential bacteria that restore the body’s natural resistance to CDI by re-establishing the ecology of the colonic microbiome,” explained Roger Pomerantz, MD, of Seres Therapeutics, Inc., the company developing SER-109.

“Because we’re focused on treating the underlying cause of the disease, we believe we have the potential to break the cycle of recurrent CDI and have a significant impact for patients.”

SER-109 is currently being investigated in a phase 2 trial. In addition to orphan designation, SER-109 has breakthrough designation from the FDA.

Trials of SER-109

Researchers reported phase 1/2 results with SER-109 at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy.

The study had 2 cohorts containing 15 patients each. Patients were between 18 and 90 years old, had 3 or more laboratory-confirmed CDI episodes over 1 year, had a life expectancy greater than 3 months, and were able to give informed consent.

Patients in cohort 1 received a mean SER-109 dose of 1.5 x 10⁹ spores, and those in cohort 2 received a mean dose of 1 x 10⁸ spores. SER-109 was deemed effective if patients did not have a CDI recurrence in the 8-week period after they received SER-109.

In cohort 1, 87% of patients (13/15) achieved the efficacy endpoint. Two patients had transient, self-limited diarrhea with a positive C difficile test, but both reached the week 8 endpoint without needing antibiotic therapy for CDI. Thus, in cohort 1, the clinical cure rate was 100%.

In cohort 2, 93% of patients (14/15) reached the 8-week endpoint CDI-free. One patient failed per protocol.

The researchers said there were no drug-related serious adverse events in this trial.

Seres Therapeutics is currently conducting a multicenter, randomized, placebo-controlled, phase 2 study (ECOSPOR) to assess the efficacy and safety of SER-109 in preventing recurrent CDI. The company expects results from this study to be available mid-2016.

About orphan and breakthrough designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

The FDA’s breakthrough therapy designation is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

The benefits of breakthrough designation include the same benefits as fast track designation—priority review of a new drug application, rolling review, etc.—plus an organizational commitment involving the FDA’s senior managers with more intensive guidance from the FDA.

Clostridium difficile spores

The US Food and Drug Administration (FDA) has granted orphan designation to SER-109 for the prevention of recurrent Clostridium difficile infection (CDI) in adults.

SER-109 is a microbiome therapeutic designed to treat recurrent CDI by correcting dysbiosis of the human microbiome.

In a single dose of 4 capsules, SER-109 re-introduces an ecology of purified bacterial spores that should restore the microbiome to a healthy state, allowing it to carry out key biological functions, including resisting Clostridium difficile.

“SER-109 is intended to re-introduce essential bacteria that restore the body’s natural resistance to CDI by re-establishing the ecology of the colonic microbiome,” explained Roger Pomerantz, MD, of Seres Therapeutics, Inc., the company developing SER-109.

“Because we’re focused on treating the underlying cause of the disease, we believe we have the potential to break the cycle of recurrent CDI and have a significant impact for patients.”

SER-109 is currently being investigated in a phase 2 trial. In addition to orphan designation, SER-109 has breakthrough designation from the FDA.

Trials of SER-109

Researchers reported phase 1/2 results with SER-109 at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy.

The study had 2 cohorts containing 15 patients each. Patients were between 18 and 90 years old, had 3 or more laboratory-confirmed CDI episodes over 1 year, had a life expectancy greater than 3 months, and were able to give informed consent.

Patients in cohort 1 received a mean SER-109 dose of 1.5 x 10⁹ spores, and those in cohort 2 received a mean dose of 1 x 10⁸ spores. SER-109 was deemed effective if patients did not have a CDI recurrence in the 8-week period after they received SER-109.

In cohort 1, 87% of patients (13/15) achieved the efficacy endpoint. Two patients had transient, self-limited diarrhea with a positive C difficile test, but both reached the week 8 endpoint without needing antibiotic therapy for CDI. Thus, in cohort 1, the clinical cure rate was 100%.

In cohort 2, 93% of patients (14/15) reached the 8-week endpoint CDI-free. One patient failed per protocol.

The researchers said there were no drug-related serious adverse events in this trial.

Seres Therapeutics is currently conducting a multicenter, randomized, placebo-controlled, phase 2 study (ECOSPOR) to assess the efficacy and safety of SER-109 in preventing recurrent CDI. The company expects results from this study to be available mid-2016.

About orphan and breakthrough designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

The FDA’s breakthrough therapy designation is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

The benefits of breakthrough designation include the same benefits as fast track designation—priority review of a new drug application, rolling review, etc.—plus an organizational commitment involving the FDA’s senior managers with more intensive guidance from the FDA.

Clostridium difficile spores

The US Food and Drug Administration (FDA) has granted orphan designation to SER-109 for the prevention of recurrent Clostridium difficile infection (CDI) in adults.

SER-109 is a microbiome therapeutic designed to treat recurrent CDI by correcting dysbiosis of the human microbiome.

In a single dose of 4 capsules, SER-109 re-introduces an ecology of purified bacterial spores that should restore the microbiome to a healthy state, allowing it to carry out key biological functions, including resisting Clostridium difficile.

“SER-109 is intended to re-introduce essential bacteria that restore the body’s natural resistance to CDI by re-establishing the ecology of the colonic microbiome,” explained Roger Pomerantz, MD, of Seres Therapeutics, Inc., the company developing SER-109.

“Because we’re focused on treating the underlying cause of the disease, we believe we have the potential to break the cycle of recurrent CDI and have a significant impact for patients.”

SER-109 is currently being investigated in a phase 2 trial. In addition to orphan designation, SER-109 has breakthrough designation from the FDA.

Trials of SER-109

Researchers reported phase 1/2 results with SER-109 at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy.

The study had 2 cohorts containing 15 patients each. Patients were between 18 and 90 years old, had 3 or more laboratory-confirmed CDI episodes over 1 year, had a life expectancy greater than 3 months, and were able to give informed consent.

Patients in cohort 1 received a mean SER-109 dose of 1.5 x 10⁹ spores, and those in cohort 2 received a mean dose of 1 x 10⁸ spores. SER-109 was deemed effective if patients did not have a CDI recurrence in the 8-week period after they received SER-109.

In cohort 1, 87% of patients (13/15) achieved the efficacy endpoint. Two patients had transient, self-limited diarrhea with a positive C difficile test, but both reached the week 8 endpoint without needing antibiotic therapy for CDI. Thus, in cohort 1, the clinical cure rate was 100%.

In cohort 2, 93% of patients (14/15) reached the 8-week endpoint CDI-free. One patient failed per protocol.

The researchers said there were no drug-related serious adverse events in this trial.

Seres Therapeutics is currently conducting a multicenter, randomized, placebo-controlled, phase 2 study (ECOSPOR) to assess the efficacy and safety of SER-109 in preventing recurrent CDI. The company expects results from this study to be available mid-2016.

About orphan and breakthrough designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

The FDA’s breakthrough therapy designation is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

The benefits of breakthrough designation include the same benefits as fast track designation—priority review of a new drug application, rolling review, etc.—plus an organizational commitment involving the FDA’s senior managers with more intensive guidance from the FDA.

Lab mice

Photo by Aaron Logan

New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.

Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.

The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.

Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.

Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.

“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.

Experiments with JQ1

To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.

The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.

“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.

Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.

“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.

To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.

After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.

Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.

Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.

Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.

Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.

Lab mice

Photo by Aaron Logan

New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.

Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.

The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.

Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.

Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.

“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.

Experiments with JQ1

To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.

The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.

“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.

Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.

“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.

To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.

After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.

Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.

Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.

Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.

Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.

Lab mice

Photo by Aaron Logan

New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.

Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.

The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.

Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.

Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.

“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.

Experiments with JQ1

To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.

The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.

“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.

Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.

“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.

To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.

After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.

Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.

Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.

Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.

Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.

The Food and Drug Administration has extended its approval of Promacta (eltrombopag) to include pediatric patients with chronic immune thrombocytopenic purpura, the agency announced Aug. 24.

Approved in 2008 for adults with immune thrombocytopenic purpura (ITP), eltrombopag is now approved for the treatment of the rare blood disorder in patients aged 1 year and older. The drug may be used in children who have not responded to other ITP medications or spleen surgery, the FDA said in a statement.

Eltrombopag’s efficacy and safety in children aged 1-17 years was established in two placebo-controlled trials comprising 159 patients. Findings from the first trial found that over 7 weeks, 62% of patients given eltrombopag had improved platelet counts without rescue therapy between weeks 1 and 6, compared with 32% in the placebo group.

In the second trial, which lasted 13 weeks, 41% of patients taking eltrombopag experienced increased platelet counts for at least 6 out of 8 weeks between weeks 5 and 12, compared with 3% of patients in the placebo group, the FDA reported.

“In both trials, patients taking Promacta also had less need for other treatments to increase their platelet counts, such as corticosteroids or platelet transfusions,” the FDA said. “Among patients taking one or more ITP medications at the start of the trials, about half were able to reduce or discontinue their use of these medications, primarily corticosteroids.”

Eltrombopag may be taken once daily in tablet form, or as a powder mixed with liquid for children aged 1-5 years. It should be used only in ITP patients with an increased risk of bleeding.

The most common side effects in children were infections of the upper respiratory tract or nose and throat, diarrhea, abdominal pain, rash, and increase in liver enzymes.

Promacta is manufactured by Novartis in East Hanover, N.J.

[email protected]

The Food and Drug Administration has extended its approval of Promacta (eltrombopag) to include pediatric patients with chronic immune thrombocytopenic purpura, the agency announced Aug. 24.

Approved in 2008 for adults with immune thrombocytopenic purpura (ITP), eltrombopag is now approved for the treatment of the rare blood disorder in patients aged 1 year and older. The drug may be used in children who have not responded to other ITP medications or spleen surgery, the FDA said in a statement.

Eltrombopag’s efficacy and safety in children aged 1-17 years was established in two placebo-controlled trials comprising 159 patients. Findings from the first trial found that over 7 weeks, 62% of patients given eltrombopag had improved platelet counts without rescue therapy between weeks 1 and 6, compared with 32% in the placebo group.

In the second trial, which lasted 13 weeks, 41% of patients taking eltrombopag experienced increased platelet counts for at least 6 out of 8 weeks between weeks 5 and 12, compared with 3% of patients in the placebo group, the FDA reported.

“In both trials, patients taking Promacta also had less need for other treatments to increase their platelet counts, such as corticosteroids or platelet transfusions,” the FDA said. “Among patients taking one or more ITP medications at the start of the trials, about half were able to reduce or discontinue their use of these medications, primarily corticosteroids.”

Eltrombopag may be taken once daily in tablet form, or as a powder mixed with liquid for children aged 1-5 years. It should be used only in ITP patients with an increased risk of bleeding.

The most common side effects in children were infections of the upper respiratory tract or nose and throat, diarrhea, abdominal pain, rash, and increase in liver enzymes.

Promacta is manufactured by Novartis in East Hanover, N.J.

[email protected]

The Food and Drug Administration has extended its approval of Promacta (eltrombopag) to include pediatric patients with chronic immune thrombocytopenic purpura, the agency announced Aug. 24.

Approved in 2008 for adults with immune thrombocytopenic purpura (ITP), eltrombopag is now approved for the treatment of the rare blood disorder in patients aged 1 year and older. The drug may be used in children who have not responded to other ITP medications or spleen surgery, the FDA said in a statement.

Eltrombopag’s efficacy and safety in children aged 1-17 years was established in two placebo-controlled trials comprising 159 patients. Findings from the first trial found that over 7 weeks, 62% of patients given eltrombopag had improved platelet counts without rescue therapy between weeks 1 and 6, compared with 32% in the placebo group.

In the second trial, which lasted 13 weeks, 41% of patients taking eltrombopag experienced increased platelet counts for at least 6 out of 8 weeks between weeks 5 and 12, compared with 3% of patients in the placebo group, the FDA reported.

“In both trials, patients taking Promacta also had less need for other treatments to increase their platelet counts, such as corticosteroids or platelet transfusions,” the FDA said. “Among patients taking one or more ITP medications at the start of the trials, about half were able to reduce or discontinue their use of these medications, primarily corticosteroids.”

Eltrombopag may be taken once daily in tablet form, or as a powder mixed with liquid for children aged 1-5 years. It should be used only in ITP patients with an increased risk of bleeding.

The most common side effects in children were infections of the upper respiratory tract or nose and throat, diarrhea, abdominal pain, rash, and increase in liver enzymes.

Promacta is manufactured by Novartis in East Hanover, N.J.

[email protected]

Peripheral plasma levels of the CNS protein tau are chronically elevated after traumatic brain injury (TBI) and appear to correlate with the severity of postconcussive symptoms, according to a report published online ahead of print August 3 in JAMA Neurology.

If these findings are confirmed, tau may be the first biomarker that is sensitive and specific to persistent TBI-related symptoms. The results also suggest that “months to years after the primary brain injury, there may be a continuation of secondary injuries with residual axonal degeneration and blood–brain barrier disruptions in this population that may contribute to the maintenance of postconcussive disorder symptoms and affect symptom severity,” said Anlys Olivera, PhD, of the National Institute of Nursing Research in Bethesda, Maryland, and her associates.

Tau stabilizes the structure of the axonal cytoskeleton. It is elevated in the CSF and the peripheral blood (albeit in extremely low concentrations) of patients with severe TBI, professional boxers, and athletes who sustain concussions. The extremely low levels of tau in the peripheral blood have been difficult to measure until the recent development of an ultrahigh-sensitivity immunoassay technology. Using this innovation, the researchers were able to examine for the first time the associations between plasma tau levels and the frequency and severity of deployment-related TBIs.

Over a two-year period, Dr. Olivera and her associates assessed tau levels in 70 members of the military who self-reported one or more TBIs and 28 military control subjects without TBI who were matched for age, sex, race, time since deployment, and number of deployments. Almost all participants in the TBI group had been injured at least 18 months previously. The most common causes of TBI were blows to the head, exposure to blasts, vehicular crashes, and sports-related concussions.

Total tau was significantly increased in the TBI group (mean level, 1.13 pg/mL), compared with the control group (0.63 pg/mL). Total tau also increased with increasing severity of the initial brain injury, with increasing number of TBIs, and with increasing severity of present-day postconcussive symptoms. These associations, moreover, were independent of symptoms of post-traumatic stress disorder and depression, which were prevalent in the TBI group, the investigators said.

Tau is not only a marker of brain injury, it also can contribute to secondary injury processes such as inflammation, which makes it a potential target for therapy. If the findings of this study are confirmed and extended to demonstrate a direct mechanistic relationship between TBI and tau aggregation, treatments such as the direct delivery of proteasomes “would be invaluable, considering the dearth of treatments for TBIs and chronic [postconcussive disorder] symptoms,” Dr. Olivera and her associates said.

Among the study limitations cited by the investigators are lack of neuroimaging and neuropsychologic data.

—Mary Ann Moon

Peripheral plasma levels of the CNS protein tau are chronically elevated after traumatic brain injury (TBI) and appear to correlate with the severity of postconcussive symptoms, according to a report published online ahead of print August 3 in JAMA Neurology.

If these findings are confirmed, tau may be the first biomarker that is sensitive and specific to persistent TBI-related symptoms. The results also suggest that “months to years after the primary brain injury, there may be a continuation of secondary injuries with residual axonal degeneration and blood–brain barrier disruptions in this population that may contribute to the maintenance of postconcussive disorder symptoms and affect symptom severity,” said Anlys Olivera, PhD, of the National Institute of Nursing Research in Bethesda, Maryland, and her associates.

Tau stabilizes the structure of the axonal cytoskeleton. It is elevated in the CSF and the peripheral blood (albeit in extremely low concentrations) of patients with severe TBI, professional boxers, and athletes who sustain concussions. The extremely low levels of tau in the peripheral blood have been difficult to measure until the recent development of an ultrahigh-sensitivity immunoassay technology. Using this innovation, the researchers were able to examine for the first time the associations between plasma tau levels and the frequency and severity of deployment-related TBIs.

Over a two-year period, Dr. Olivera and her associates assessed tau levels in 70 members of the military who self-reported one or more TBIs and 28 military control subjects without TBI who were matched for age, sex, race, time since deployment, and number of deployments. Almost all participants in the TBI group had been injured at least 18 months previously. The most common causes of TBI were blows to the head, exposure to blasts, vehicular crashes, and sports-related concussions.

Total tau was significantly increased in the TBI group (mean level, 1.13 pg/mL), compared with the control group (0.63 pg/mL). Total tau also increased with increasing severity of the initial brain injury, with increasing number of TBIs, and with increasing severity of present-day postconcussive symptoms. These associations, moreover, were independent of symptoms of post-traumatic stress disorder and depression, which were prevalent in the TBI group, the investigators said.

Tau is not only a marker of brain injury, it also can contribute to secondary injury processes such as inflammation, which makes it a potential target for therapy. If the findings of this study are confirmed and extended to demonstrate a direct mechanistic relationship between TBI and tau aggregation, treatments such as the direct delivery of proteasomes “would be invaluable, considering the dearth of treatments for TBIs and chronic [postconcussive disorder] symptoms,” Dr. Olivera and her associates said.

Among the study limitations cited by the investigators are lack of neuroimaging and neuropsychologic data.

—Mary Ann Moon

Peripheral plasma levels of the CNS protein tau are chronically elevated after traumatic brain injury (TBI) and appear to correlate with the severity of postconcussive symptoms, according to a report published online ahead of print August 3 in JAMA Neurology.

If these findings are confirmed, tau may be the first biomarker that is sensitive and specific to persistent TBI-related symptoms. The results also suggest that “months to years after the primary brain injury, there may be a continuation of secondary injuries with residual axonal degeneration and blood–brain barrier disruptions in this population that may contribute to the maintenance of postconcussive disorder symptoms and affect symptom severity,” said Anlys Olivera, PhD, of the National Institute of Nursing Research in Bethesda, Maryland, and her associates.

Tau stabilizes the structure of the axonal cytoskeleton. It is elevated in the CSF and the peripheral blood (albeit in extremely low concentrations) of patients with severe TBI, professional boxers, and athletes who sustain concussions. The extremely low levels of tau in the peripheral blood have been difficult to measure until the recent development of an ultrahigh-sensitivity immunoassay technology. Using this innovation, the researchers were able to examine for the first time the associations between plasma tau levels and the frequency and severity of deployment-related TBIs.

Over a two-year period, Dr. Olivera and her associates assessed tau levels in 70 members of the military who self-reported one or more TBIs and 28 military control subjects without TBI who were matched for age, sex, race, time since deployment, and number of deployments. Almost all participants in the TBI group had been injured at least 18 months previously. The most common causes of TBI were blows to the head, exposure to blasts, vehicular crashes, and sports-related concussions.

Total tau was significantly increased in the TBI group (mean level, 1.13 pg/mL), compared with the control group (0.63 pg/mL). Total tau also increased with increasing severity of the initial brain injury, with increasing number of TBIs, and with increasing severity of present-day postconcussive symptoms. These associations, moreover, were independent of symptoms of post-traumatic stress disorder and depression, which were prevalent in the TBI group, the investigators said.

Tau is not only a marker of brain injury, it also can contribute to secondary injury processes such as inflammation, which makes it a potential target for therapy. If the findings of this study are confirmed and extended to demonstrate a direct mechanistic relationship between TBI and tau aggregation, treatments such as the direct delivery of proteasomes “would be invaluable, considering the dearth of treatments for TBIs and chronic [postconcussive disorder] symptoms,” Dr. Olivera and her associates said.

Among the study limitations cited by the investigators are lack of neuroimaging and neuropsychologic data.

—Mary Ann Moon

The combination of lenalidomide and rituximab was more active in patients with recurrent follicular lymphoma, compared with lenalidomide alone, and significantly increased the overall response rate, according to new data published online Aug. 24 in the Journal of Clinical Oncology.

Although both lenalidomide and rituximab are active agents in follicular lymphoma, their combined use in recurrent follicular lymphoma has not been previously evaluated in randomized clinical trials, said Dr. John P. Leonard of Cornell University, New York, and his colleagues.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

The overall response rate of patients receiving the combination regimen was significantly higher than that of patients who received lenalidomide alone (P = .029). In the cohort receiving lenalidomide alone, 24 patients (53%) achieved an objective response (9 complete responses [20%]), while 35 patients (76%) in the lenalidomide/rituximab group were responders (18 complete responses [39%]).

At a median follow-up of 2.5 years (range, 0.1-4.8 years), the addition of rituximab to lenalidomide in this population also significantly increased the median time to progression: 1.1 year for lenalidomide alone versus 2 years for the combined therapy (P = .002).

Overall survival was 4.5 years for lenalidomide alone and has not yet been reached for the combination arm (P = .149.

This trial helps to establish the safety profile of single-agent lenalidomide in follicular lymphoma, while its “randomized nature also allows a direct assessment of potential toxicity resulting from the addition of rituximab to lenalidomide,” wrote Dr. Leonard and his associates (J Clin Oncol. 2015 Aug 24. doi: 10.1200/JCO.2014.59.9258).

“There was no evidence of increased toxicity from the lenalidomide/rituximab combination compared with lenalidomide alone,” they pointed out.

Both lenalidomide alone and lenalidomide/rituximab were well tolerated, with grade 3-4 adverse events occurring in 58% and 53% of patients, respectively, with 9% and 11% of patients experiencing grade 4 toxicity, respectively. The most common grade 3-4 adverse events included neutropenia (16% vs. 20%), fatigue (9% vs. 13%), and rash (4% vs. 4%).

The study was supported in part by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology. Dr. Leonard reported financial relationships with Celgene and Genentech, and several coauthors also reported relationships with industry.

The combination of lenalidomide and rituximab was more active in patients with recurrent follicular lymphoma, compared with lenalidomide alone, and significantly increased the overall response rate, according to new data published online Aug. 24 in the Journal of Clinical Oncology.

Although both lenalidomide and rituximab are active agents in follicular lymphoma, their combined use in recurrent follicular lymphoma has not been previously evaluated in randomized clinical trials, said Dr. John P. Leonard of Cornell University, New York, and his colleagues.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

The overall response rate of patients receiving the combination regimen was significantly higher than that of patients who received lenalidomide alone (P = .029). In the cohort receiving lenalidomide alone, 24 patients (53%) achieved an objective response (9 complete responses [20%]), while 35 patients (76%) in the lenalidomide/rituximab group were responders (18 complete responses [39%]).

At a median follow-up of 2.5 years (range, 0.1-4.8 years), the addition of rituximab to lenalidomide in this population also significantly increased the median time to progression: 1.1 year for lenalidomide alone versus 2 years for the combined therapy (P = .002).

Overall survival was 4.5 years for lenalidomide alone and has not yet been reached for the combination arm (P = .149.

This trial helps to establish the safety profile of single-agent lenalidomide in follicular lymphoma, while its “randomized nature also allows a direct assessment of potential toxicity resulting from the addition of rituximab to lenalidomide,” wrote Dr. Leonard and his associates (J Clin Oncol. 2015 Aug 24. doi: 10.1200/JCO.2014.59.9258).

“There was no evidence of increased toxicity from the lenalidomide/rituximab combination compared with lenalidomide alone,” they pointed out.

Both lenalidomide alone and lenalidomide/rituximab were well tolerated, with grade 3-4 adverse events occurring in 58% and 53% of patients, respectively, with 9% and 11% of patients experiencing grade 4 toxicity, respectively. The most common grade 3-4 adverse events included neutropenia (16% vs. 20%), fatigue (9% vs. 13%), and rash (4% vs. 4%).

The study was supported in part by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology. Dr. Leonard reported financial relationships with Celgene and Genentech, and several coauthors also reported relationships with industry.

The combination of lenalidomide and rituximab was more active in patients with recurrent follicular lymphoma, compared with lenalidomide alone, and significantly increased the overall response rate, according to new data published online Aug. 24 in the Journal of Clinical Oncology.

Although both lenalidomide and rituximab are active agents in follicular lymphoma, their combined use in recurrent follicular lymphoma has not been previously evaluated in randomized clinical trials, said Dr. John P. Leonard of Cornell University, New York, and his colleagues.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

The overall response rate of patients receiving the combination regimen was significantly higher than that of patients who received lenalidomide alone (P = .029). In the cohort receiving lenalidomide alone, 24 patients (53%) achieved an objective response (9 complete responses [20%]), while 35 patients (76%) in the lenalidomide/rituximab group were responders (18 complete responses [39%]).

At a median follow-up of 2.5 years (range, 0.1-4.8 years), the addition of rituximab to lenalidomide in this population also significantly increased the median time to progression: 1.1 year for lenalidomide alone versus 2 years for the combined therapy (P = .002).

Overall survival was 4.5 years for lenalidomide alone and has not yet been reached for the combination arm (P = .149.

This trial helps to establish the safety profile of single-agent lenalidomide in follicular lymphoma, while its “randomized nature also allows a direct assessment of potential toxicity resulting from the addition of rituximab to lenalidomide,” wrote Dr. Leonard and his associates (J Clin Oncol. 2015 Aug 24. doi: 10.1200/JCO.2014.59.9258).

“There was no evidence of increased toxicity from the lenalidomide/rituximab combination compared with lenalidomide alone,” they pointed out.

Both lenalidomide alone and lenalidomide/rituximab were well tolerated, with grade 3-4 adverse events occurring in 58% and 53% of patients, respectively, with 9% and 11% of patients experiencing grade 4 toxicity, respectively. The most common grade 3-4 adverse events included neutropenia (16% vs. 20%), fatigue (9% vs. 13%), and rash (4% vs. 4%).

The study was supported in part by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology. Dr. Leonard reported financial relationships with Celgene and Genentech, and several coauthors also reported relationships with industry.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

The Diagnosis: Phrynoderma

Phrynoderma, meaning “toad skin,” was first described by Nicholls¹ in 1933 as a condition due to vitamin A deficiency and characterized by follicular hyperkeratosis. Since then, there has been debate in the literature over the etiology of phrynoderma, as studies have demonstrated different causes for this condition,^2-5 which suggests that it is prudent to check several markers of nutritional status including vitamin A, vitamin B, vitamin E, and essential fatty acid studies.

Phrynoderma is most commonly seen in South and East Asia with relatively rare occurrences in the United States. Although it characteristically occurs in children and adolescents aged 5 to 15 years, almost all of the cases reported in the United States have occurred in adults.^6,7 A clear gender predilection has not been established.⁷

Phrynoderma tends to favor the extensor surfaces. In particular, the elbows, thighs, and buttocks are the most commonly affected locations. The face is typically the last site to become involved. On physical examination of a patient with phrynoderma, there are various-sized, discrete, red-brown to flesh-colored papules with a conical keratotic follicular plug (Figure).³ The eruption is often asymptomatic, but mild pruritus may be reported.⁷ Additional signs of vitamin A deficiency may be present, including night blindness, hyperpigmentation, or xerosis. Patients with phrynoderma also may have evidence of other nutritional deficiencies, such as angular stomatitis, cheilitis, or glossitis. The differential diagnosis for a patient with this type of papular eruption may include pityriasis rubra pilaris, keratosis pilaris, lichen spinulosus, crusted scabies, and follicular lichen planus.⁷ History and clinical presentation can generally help to distinguish these diagnoses.

Generalized follicular, erythematous, and scaly papular eruption on the chest (A) and abdomen (B).

Histopathology typically shows moderate hyperkeratosis with distension of the upper portion of the follicle by large keratotic plugs. Sebaceous glands are greatly reduced in size and may exhibit epithelial atrophy.^8,9

A reduced serum vitamin A level can confirm the diagnosis of phrynoderma. Our patient’s laboratory results revealed a vitamin A value of 26 mg/100 dL (reference range, 38–106 mg/100 dL), consistent with his clinical presentation of phrynoderma. Other markers of nutritional status, including vitamins D, E, and K₁, were all within reference range. Treatment consists of replacing the nutritional deficit. High doses of vitamin A, such as 200,000 to 500,000 IU daily for 3 to 5 days or daily doses of 2000 to 50,000 IU, can lead to resolution of the rash in 1 to 4 months.^8,9 Our patient was started on 10,000 IU of oral vitamin A daily at discharge but unfortunately died a few months later.

Vitamin A has been shown to promote maturation and differentiation of the basal keratinocytes as they move up through the epidermis, which may in part explain why this treatment is effective.¹⁰ It is important to be aware of this condition when seeing a patient with follicular hyperkeratosis because even patients in developed countries with malnutrition due to diet or gastrointestinal disease may develop phrynoderma.

The Diagnosis: Phrynoderma

Phrynoderma, meaning “toad skin,” was first described by Nicholls¹ in 1933 as a condition due to vitamin A deficiency and characterized by follicular hyperkeratosis. Since then, there has been debate in the literature over the etiology of phrynoderma, as studies have demonstrated different causes for this condition,^2-5 which suggests that it is prudent to check several markers of nutritional status including vitamin A, vitamin B, vitamin E, and essential fatty acid studies.

Phrynoderma is most commonly seen in South and East Asia with relatively rare occurrences in the United States. Although it characteristically occurs in children and adolescents aged 5 to 15 years, almost all of the cases reported in the United States have occurred in adults.^6,7 A clear gender predilection has not been established.⁷

Phrynoderma tends to favor the extensor surfaces. In particular, the elbows, thighs, and buttocks are the most commonly affected locations. The face is typically the last site to become involved. On physical examination of a patient with phrynoderma, there are various-sized, discrete, red-brown to flesh-colored papules with a conical keratotic follicular plug (Figure).³ The eruption is often asymptomatic, but mild pruritus may be reported.⁷ Additional signs of vitamin A deficiency may be present, including night blindness, hyperpigmentation, or xerosis. Patients with phrynoderma also may have evidence of other nutritional deficiencies, such as angular stomatitis, cheilitis, or glossitis. The differential diagnosis for a patient with this type of papular eruption may include pityriasis rubra pilaris, keratosis pilaris, lichen spinulosus, crusted scabies, and follicular lichen planus.⁷ History and clinical presentation can generally help to distinguish these diagnoses.

Generalized follicular, erythematous, and scaly papular eruption on the chest (A) and abdomen (B).

Histopathology typically shows moderate hyperkeratosis with distension of the upper portion of the follicle by large keratotic plugs. Sebaceous glands are greatly reduced in size and may exhibit epithelial atrophy.^8,9

A reduced serum vitamin A level can confirm the diagnosis of phrynoderma. Our patient’s laboratory results revealed a vitamin A value of 26 mg/100 dL (reference range, 38–106 mg/100 dL), consistent with his clinical presentation of phrynoderma. Other markers of nutritional status, including vitamins D, E, and K₁, were all within reference range. Treatment consists of replacing the nutritional deficit. High doses of vitamin A, such as 200,000 to 500,000 IU daily for 3 to 5 days or daily doses of 2000 to 50,000 IU, can lead to resolution of the rash in 1 to 4 months.^8,9 Our patient was started on 10,000 IU of oral vitamin A daily at discharge but unfortunately died a few months later.

Vitamin A has been shown to promote maturation and differentiation of the basal keratinocytes as they move up through the epidermis, which may in part explain why this treatment is effective.¹⁰ It is important to be aware of this condition when seeing a patient with follicular hyperkeratosis because even patients in developed countries with malnutrition due to diet or gastrointestinal disease may develop phrynoderma.

The Diagnosis: Phrynoderma

Phrynoderma, meaning “toad skin,” was first described by Nicholls¹ in 1933 as a condition due to vitamin A deficiency and characterized by follicular hyperkeratosis. Since then, there has been debate in the literature over the etiology of phrynoderma, as studies have demonstrated different causes for this condition,^2-5 which suggests that it is prudent to check several markers of nutritional status including vitamin A, vitamin B, vitamin E, and essential fatty acid studies.

Phrynoderma is most commonly seen in South and East Asia with relatively rare occurrences in the United States. Although it characteristically occurs in children and adolescents aged 5 to 15 years, almost all of the cases reported in the United States have occurred in adults.^6,7 A clear gender predilection has not been established.⁷

Phrynoderma tends to favor the extensor surfaces. In particular, the elbows, thighs, and buttocks are the most commonly affected locations. The face is typically the last site to become involved. On physical examination of a patient with phrynoderma, there are various-sized, discrete, red-brown to flesh-colored papules with a conical keratotic follicular plug (Figure).³ The eruption is often asymptomatic, but mild pruritus may be reported.⁷ Additional signs of vitamin A deficiency may be present, including night blindness, hyperpigmentation, or xerosis. Patients with phrynoderma also may have evidence of other nutritional deficiencies, such as angular stomatitis, cheilitis, or glossitis. The differential diagnosis for a patient with this type of papular eruption may include pityriasis rubra pilaris, keratosis pilaris, lichen spinulosus, crusted scabies, and follicular lichen planus.⁷ History and clinical presentation can generally help to distinguish these diagnoses.

Generalized follicular, erythematous, and scaly papular eruption on the chest (A) and abdomen (B).

Histopathology typically shows moderate hyperkeratosis with distension of the upper portion of the follicle by large keratotic plugs. Sebaceous glands are greatly reduced in size and may exhibit epithelial atrophy.^8,9

A reduced serum vitamin A level can confirm the diagnosis of phrynoderma. Our patient’s laboratory results revealed a vitamin A value of 26 mg/100 dL (reference range, 38–106 mg/100 dL), consistent with his clinical presentation of phrynoderma. Other markers of nutritional status, including vitamins D, E, and K₁, were all within reference range. Treatment consists of replacing the nutritional deficit. High doses of vitamin A, such as 200,000 to 500,000 IU daily for 3 to 5 days or daily doses of 2000 to 50,000 IU, can lead to resolution of the rash in 1 to 4 months.^8,9 Our patient was started on 10,000 IU of oral vitamin A daily at discharge but unfortunately died a few months later.

Vitamin A has been shown to promote maturation and differentiation of the basal keratinocytes as they move up through the epidermis, which may in part explain why this treatment is effective.¹⁰ It is important to be aware of this condition when seeing a patient with follicular hyperkeratosis because even patients in developed countries with malnutrition due to diet or gastrointestinal disease may develop phrynoderma.